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Int J Oncol. 2018 Nov;53(5):1881-1896. doi: 10.3892/ijo.2018.4528. Epub 2018 Aug 16.

Inhibition of PI3K signalling increases the efficiency of radiotherapy in glioblastoma cells.

Author information

1
Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, D-89075 Ulm, Germany.
2
Department of Neurosurgery, University Medical Center Ulm, D-89075 Ulm, Germany.
3
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
4
Department of Clinical Chemistry, University Medical Center Ulm, D-89075 Ulm, Germany.
5
Department of Radiology, German Armed Forces Hospital of Ulm, D-89081 Ulm, Germany.

Abstract

Glioblastoma, the most common primary brain tumour, is also considered one of the most lethal cancers per se. It is highly refractory to therapeutic intervention, as highlighted by the mean patient survival of only 15 months, despite an aggressive treatment approach, consisting of maximal safe surgical resection, followed by radio- and chemotherapy. Radiotherapy, in particular, can have effects on the surviving fractions of tumour cells, which are considered adverse to the desired clinical outcome: It can induce increased cellular proliferation, as well as enhanced invasion. In this study, we established that differentiated glioblastoma cells alter their DNA repair response following repeated exposure to radiation and, therefore, high single-dose irradiationĀ (SD-IR) is not a good surrogate marker for fractionated dose irradiationĀ (FD-IR), as used in clinical practice. Integrating irradiation into a combination therapy approach, we then investigated whether the pharmacological inhibition of PI3K signalling, the most abundantly activated survival cascade in glioblastoma, enhances the efficacy of radiotherapy. Of note, treatment with GDC-0941, which blocks PI3K-mediated signalling, did not enhance cell death upon irradiation, but both treatment modalities functioned synergistically to reduce the total cell number. Furthermore, GDC-0941 not only prevented the radiation-induced increase in the motility of the differentiated cells, but further reduced their speed below that of untreated cells. Therefore, combining radiotherapy with the pharmacological inhibition of PI3K signalling is a potentially promising approach for the treatment of glioblastoma, as it can reduce the unwanted effects on the surviving fraction of tumour cells.

PMID:
30132519
DOI:
10.3892/ijo.2018.4528

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